Advances in gene recombination technology have enabled the pharmaceutical use of antibodies such as immunoglobulins, monoclonal antibodies and humanized antibodies. To ensure a stable supply of these antibodies, it is necessary to establish production and storage conditions where the structure and activity of the antibodies can be maintained.
When proteins are stored in a highly concentrated solution form, they are usually associated with a problem of deterioration, including the formation of insoluble aggregates, which is required to be prevented. It is necessary to prevent such deterioration. For example, the applicant has found that an anti-HM1.24 antibody has a therapeutic effect on myeloma cells (JP KOKAI 11-092399), and also has studied formulation of this antibody. However, the anti-HM1.24 antibody is an unstable protein and is more likely to undergo physical and chemical changes (e.g., association, aggregation) as a result of stresses in the purification process. Such stresses include filtration stress during removal of virus and bacteria, concentration stress, heat stress and light stress.
Also, in the case of using genetic engineering techniques to obtain antibodies, antibody-producing cells are cultured in bulk, the antibody-containing solutions are purified, frozen and stored until thawing for use in drug formulation. However, repeating such shaking and freezing-thawing steps causes the formation of antibody aggregates and/or insoluble particles. Furthermore, long-term storage causes decomposition of antibodies, resulting in formation of decomposition products. These phenomena could eventually lead to a reduced level of antibodies remaining in the solution.
There is also a problem that visible insoluble matter and insoluble particles are formed in the presence of metal ions (Fe ions) introduced during the production process. Since metal ions (Fe ions), even when present in very small amounts in the solution, contribute to the formation of visible insoluble matter and insoluble particles, such ions should be removed completely. However, there is a limit to removal methods such as precipitation, complex formation, and so on. Thus, there has been a need to develop a strategy to avoid the formation of visible insoluble matter and insoluble particles even in the presence of metal ions.
Many attempts have been made to store proteins in a solution form, with the finding that stabilization effects are obtained by addition of a stabilizer for preventing chemical and physical changes. Examples of a stabilizer include high-molecular weight materials such as proteins (e.g., human serum albumin, purified gelatin) or low-molecular weight materials such as polyols, amino acids and surfactants. However, when added as stabilizers, organism-derived high-molecular weight materials like proteins are disadvantageous in that very complicated processes are required to remove contaminants, such as viruses and prions. With respect to low-molecular weight materials, it is also preferable to use them in as small amounts as possible.
For stabilization of lyophilized antibody formulations, there has been reported those comprising a sugar or amino sugar, an amino acid, and a surfactant as stabilizers (JP TOKUHYO 2001-503781).
However, there has been a strong demand for easy-to-use solution formulations that eliminates of dissolution and reconstitution steps before use. Especially, there has been a need for stable solution formulations containing antibodies.